Barrett Alison, Shingare Manisha R, Rechtsteiner Andreas, Wijeratne Tilini U, Rodriguez Kelsie M, Rubin Seth M, Müller Gerd A
Department of Chemistry and Biochemistry, University of California, Santa Cruz, CA 95064, USA.
Current Affiliation: Department of Medicine, Division of Immunology and Rheumatology, Stanford University, Stanford, CA 94305, USA.
bioRxiv. 2023 Oct 28:2023.10.28.564489. doi: 10.1101/2023.10.28.564489.
Histone deacetylases (HDACs) are pivotal in transcriptional regulation, and their dysregulation has been associated with various diseases including cancer. One of the critical roles of HDAC-containing complexes is the deacetylation of histone tails, which is canonically linked to transcriptional repression. Previous research has indicated that HDACs are recruited to cell-cycle gene promoters through the RB protein or the DREAM complex via SIN3B and that HDAC activity is essential for repressing G1/S and G2/M cell-cycle genes during cell-cycle arrest and exit. In this study, we sought to explore the interdependence of DREAM, RB, SIN3 proteins, and HDACs in the context of cell-cycle gene repression. We found that genetic knockout of SIN3B did not lead to derepression of cell-cycle genes in non-proliferating HCT116 and C2C12 cells. A combined loss of SIN3A and SIN3B resulted in a moderate upregulation in mRNA expression of several cell-cycle genes in arrested HCT116 cells, however, these effects appeared to be independent of DREAM or RB. Furthermore, HDAC inhibition did not induce a general upregulation of RB and DREAM target gene expression in arrested transformed or non-transformed cells. Our findings provide evidence that E2F:RB and DREAM complexes can repress cell-cycle genes without reliance on HDAC activity.
组蛋白去乙酰化酶（HDACs）在转录调控中起关键作用，其失调与包括癌症在内的多种疾病相关。含HDAC的复合物的关键作用之一是组蛋白尾巴的去乙酰化，这通常与转录抑制有关。先前的研究表明，HDACs通过RB蛋白或经由SIN3B的DREAM复合物被招募到细胞周期基因启动子上，并且HDAC活性对于在细胞周期停滞和退出期间抑制G1/S和G2/M细胞周期基因至关重要。在本研究中，我们试图探讨在细胞周期基因抑制的背景下DREAM、RB、SIN3蛋白和HDACs之间的相互依赖性。我们发现，在非增殖性HCT116和C2C12细胞中，SIN3B的基因敲除不会导致细胞周期基因的去抑制。SIN3A和SIN3B的联合缺失导致停滞的HCT116细胞中几个细胞周期基因的mRNA表达适度上调，然而，这些作用似乎独立于DREAM或RB。此外，HDAC抑制并未在停滞的转化或未转化细胞中诱导RB和DREAM靶基因表达的普遍上调。我们的研究结果提供了证据，表明E2F:RB和DREAM复合物可以在不依赖HDAC活性的情况下抑制细胞周期基因。
